The goal of this proposal is to identify the earliest melanoma precursors and to study the mechanisms of intraepidermal melanoma progression. Recent studies have identified a field effect comprised of genetically abnormal melanocytes in the non-lesional skin adjacent to primary melanomas. Evidence suggests that these field cells may be a source of local recurrences. The field effect appears to be confined to melanomas with a lentiginous growth pattern i.e. an intraepidermal growth pattern in which melanocytes are arranged as single units within the basilar epidermis such as acral and lentigo maligna melanomas. These melanoma types frequently have activating genetic alterations in the KIT signaling pathway. Since KIT has an essential role in melanocyte migration and homing of melanoblasts to the basal dermis, the hypothesis is that KIT pathway activation represents the initiating event that is subsequently followed by the acquisition of additional genetic alterations required to form clinically and histologically detectable lesions. To test this hypothesis, the candidate has developed a xenograft model of early human melanoma progression. Specifically, she will study the intraepidermal migration of genetically engineered melanocytes and melanoma cells expressing relevant KIT mutations seeded into human skin reconstructs grafted onto immunodeficient mice. In parallel, the candidate will evaluate the impact of KIT inhibitors on intraepidermal melanoma progression. These studies will provide an explanation for the tendency of certain melanoma types to recur after apparently complete excision and will offer the possibility to use KIT inhibitors to treat early melanoma.